Mice infected with the gram negative bacterium Salmonella typhimurium develop a systemic disease of the reticuloendothelial cell system (RES) that resembles typhoid fever in man. Although mice of some inbred strains invariably die when challenged with low-doses (less than 10 bacteria) of virulent salmonella, mice of other inbred strains survive infection with 10,000 organisms. Four host genes have been identified which regulate this differential susceptibility. These genes include: Ity, a mouse Chromosome 1 locus, that regulates the extent of S. typhimurium growth in RES macrophages; Lpsd, a defective allele of a Chromosome 4 gene that confers LPS hyporesponsiveness and salmonellae susceptibility; sid, and X-linked gene that renders mice susceptible to salmonellae apparently because of a defective antibody response to the bacterium; and an unmapped autosomal gene that is expressed by C57L mice as late-phase susceptibility to murine typhoid. The goal of this project is to further define the mechanisms whereby these genes control susceptibility to salmonellosis. The following experiments are proposed to achieve this aim. First, the basis for the slower net growth of S. typhimurium in Ityr than in Itys macrophages will be examined by tests for differences in microbicidal enzyme activities, availability of nutrients for bacterial replication, and location of salmonellae within macrophages. Second, the ability of Lpsd mice to kill and phagocytose S. typhimurium will be evaluated by in vivo and in vitro studies with radiolabeled bacteria and with a temperature-sensitive mutant of S. typhimurium. Third, the nature of the xid anti-salmonella antibody defect will be further characterized and the requirement for protective antibody in long-term survival after S. typhimurium challenge assessed by in vivo and in vitro studies. Fourth, the immunological basis for the late-stage susceptibility of C57L mice to murine typhoid will be investigated by tests of the antibody and cell-mediated immune response of these mice to the microbe. Fifth, the reasons for the intraspecies resistance of mice to S. typhi, the agent of human typhoid, will be explored by in vitro macrophage assays with S. typhi-S. typhimurium hybrid bacteria. The long-term goal of this investigation is to identify the products of host genes that modulate resistance to murine typhoid. The results of these studies will serve as a model for the genetic regulation of resistance to an infectious agent and will also increase our understanting of mechanisms of immunity to typhoid fever.